Monoclonal antibodies (MAb), by virtue of their unique in-vitro specificity and high affinity for their antigen, have generally been considered particularly attractive as selective carriers of cancer radiodiagnostic/therapeutic agents. Several reasons underlie these expectations: (i) they show a high degree of specificity and affinity for their intended target; (ii) they are generally nontoxic; and (iii) they can transport such agents. The application of MAb in animals and humans for both tumor scintigraphic detection (labeled with 123I, 131I, 93mTc, and 111In) and therapy (labeled with the beta emitters 131I, 186Re, 90Y, 165Dy, 67Cu, and 109Pd; the alpha emitters 211At, 212Bi, and 213Bi; or conjugated to various toxins and cytotoxic drugs) is the focus of work in many research laboratories.
In pursuing these studies, the basic assumption continues to be that MAb have a role in the radioimmunodiagnosis and radioimmunotherapy of cancer. However, while most published work on this subject has demonstrated their utility in the diagnosis and treatment of various tumors in experimental animal models, the use of radiolabeled MAb to target and treat solid tumors in cancer patients has been for the most part unsuccessful. There are at least five reasons for the results seen in humans:
1. Low tumor uptake. Thus far, most studies in humans have demonstrated that the percentage injected dose per gram of tumor (% ID/g) is extremely low. As a result, the absolute amount of the therapeutic radionuclide within the tumor is much less than that needed to deposit a radiation dose sufficiently high to sterilize the tumor.
2. High activity in the whole body. A corollary to low tumor uptake is the presence of ˜90%-99% of the injected radiolabeled MAb in the rest of the body. This has led to the deposition of high doses in normal tissues and unacceptable side effects, and a reduction in the maximum tolerated dose (MTD).
3. Slow blood clearance. In most human radioimmunotherapy trials, whole MAb (MW˜150,000 Da) have been used. The clearance of such high-molecular-weight proteins from blood and nontargeted tissues is rather slow. The resulting systemic exposure to the radioisotope thus produces high doses to the bone marrow and a lowering of the MTD.
4. Limited intratumoral diffusion. The high molecular weight of MAb also limits their ability to extravasate and diffuse through the tumor mass. As a consequence, many areas within the tumor are spared from receiving a lethal dose of radiation (i.e., the areas are either outside the range of the emitted particle or receive a sublethal dose).
5. Heterogeneity of tumor-associated antigen expression. Many studies have demonstrated that a substantial proportion of the cells within a tumor mass show reduced/no expression of the targeted antigen. This also will lead to nonuniform distribution of the radionuclide within the tumor mass and the sparing of a large number of cells within the tumor.
In an attempt to bypass some of the limitations of these unique molecules, various two-step and three-step approaches have been theorized, in which a noninternalizing antitumor antibody is injected prior to the administration of a low-molecular-weight therapeutic molecule that has an affinity/reactivity with the preinjected antibody molecule. These systems can be categorized into two major classes: MAb-directed enzyme prodrug therapy and MAb-directed radioligand targeting, details of which are known in the art.
It is clear that under ideal conditions, a radiolabeled therapeutic agent must meet the following requirements: (i) be labeled with an energetic particle emitter, (ii) be taken up rapidly and efficiently by the tumor, (iii) be retained by the tumor (i.e. very long effective clearance half-life), (iv) have a short residence within normal tissues (i.e., short effective half-life in blood, bone marrow, and whole body), (v) achieve high tumor-to-normal tissue uptake ratios, (vi) attain an intratumoral distribution that is sufficiently uniform to match the range of the emitted particles (i.e. all tumor cells are within the range of the emitted particles), and (vii) achieve an intratumoral concentration that is sufficiently high to deposit a tumoricidal dose in every cell that is within the range of the emitted particle.